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The effect of the antisickling compound GBT1118 on the permeability of red blood cells from patients with sickle cell anemia.

Accepted version
Peer-reviewed

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Authors

Al Balushi, Halima 
Dufu, Kobina 
Rees, David C 
Brewin, John N 

Abstract

Sickle cell anemia (SCA) is one of the commonest severe inherited disorders. Nevertheless, effective treatments remain inadequate and novel ones are avidly sought. A promising advance has been the design of novel compounds which react with hemoglobin S (HbS) to increase oxygen (O2 ) affinity and reduce sickling. One of these, voxelotor (GBT440), is currently in advanced clinical trials. A structural analogue, GBT1118, was investigated in the current work. As RBC dehydration is important in pathogenesis of SCA, the effect of GBT1118 on RBC cation permeability was also studied. Activities of Psickle , the Gardos channel and the KCl cotransporter (KCC) were all reduced. Gardos channel and KCC activities were also inhibited in RBCs treated with Ca2+ ionophore or the thiol reagent N-ethylmaleimide, indicative of direct effects on these two transport systems. Consistent with its action on RBC membrane transporters, GBT1118 significantly increased RBC hydration. RBC hemolysis was reduced in a nonelectrolyte lysis assay. Further to its direct effects on O2 affinity, GBT1118 was therefore found to reduce RBC shrinkage and fragility. Findings reveal important effects of GBT1118 on protecting sickle cells and suggest that this is approach may represent a useful therapy for amelioration of the clinical complications of SCA.

Description

Keywords

GBT1118, O2 affinity, Sickle cell anemia, cell volume, hemolysis, potassium permeability, sickling, Anemia, Sickle Cell, Antisickling Agents, Benzaldehydes, Cell Size, Erythrocyte Membrane, Hemoglobin, Sickle, Hemolysis, Humans, Intermediate-Conductance Calcium-Activated Potassium Channels, Niacinamide, Oxygen, Permeability, Symporters, K Cl- Cotransporters

Journal Title

Physiol Rep

Conference Name

Journal ISSN

2051-817X
2051-817X

Volume Title

7

Publisher

Wiley
Sponsorship
British Heart Foundation (None)
British Heart Foundation (PG/15/118/31966)
Sultanate of Oman His Majesty Sultan Qaboos's 1000 grants British Heart Foundation